6-substituted amino-4H-pyrano(3,2-G)quinoline-2,8-dicarboxylic acid intermediates

ABSTRACT

Disclosed are compounds of the formula ##STR1## in which R is hydrogen or alkyl C 1  to C 6  and R 5  and R 10 , which may be the same or different, are hydrogen or alkyl C 1  to C 6 , 
     X represents a group --AR 6 , 
     A is CO or SO 2  and R 6  is halogen, C 1  -C 6  haloalkyl, C 1  -C 6  alkoxy, C 6  -C 9  aryloxy or phenyl optionally substituted by C 1  -C 6  alkyl, and salts, esters, and amides which are intermediates to anti-allergic compounds.

This is a division of application Ser. No. 424,392, filed Sept. 27,1982, U.S. Pat. No. 4,471,119.

This invention relates to a novel process.

4-Alkylaminoquinoline derivatives are usually prepared by conversion ofthe 4-oxo group of a 4-quinolone to a leaving group, followed byreplacement of the leaving group by an alkylamine, e.g. British patentapplication number 2035312A.

However this method is inappropriate when the quinolone startingmaterial bears other functional groups which react with alkylamines,e.g. a 4-oxo-4-H-pyrano-2-carboxy ring.

According to the invention we provide a process for the production of acompound of formula I, ##STR2## in which R is hydrogen or alkyl C₁ toC₆, and R₅ and R₁₀, which may be the same or different, are eachhydrogen or alkyl C₁ to C₆,

or a pharmaceutically acceptable derivative thereof,

which comprises removal of an activating group from a compound offormula II, ##STR3## or a suitable derivative thereof, in which R, R₅and R₁₀ are as defined above, and X represents an activating group,

and if desired or necessary converting the resulting compound of formulaI to a pharmaceutically acceptable derivative thereof, or vice versa.

The activating group X may be a group --AR₆, in which A is CO or SO₂ andR₆ is halogen e.g. chlorine, haloalkyl, alkoxy C₁ -C₆, e.g. ethoxy,aryloxy C₆ -C₉, e.g. chlorophenoxy, or phenyl optionally substituted byalkyl C₁ -C₆. More specifically the activating group may be --COCCl₃,--SO₂ OR₇, where R₇ is phenyl optionally substituted by halogen, e.g.chlorine; or preferably p-toluenesulphonyl.

The removal of the activating group may be affected by hydrolysis, or byreductive cleavage, e.g. with zinc and acetic acid, or hydrogen and apalladium on charcoal catalyst. The hydrolysis may be effected underbasic, e.g. sodium hydroxide, conditions, or using acidic conditions.When the activating group is p-toluenesulphonyl, it is preferablyremoved using acidic hydrolysis, e.g. using sulphuric acid, or a mixtureof acetic and hydrobromic acids. The hydrolysis may be carried out at atemperature of from about 5° to 120° C. The hydrolysis may be carriedout in a solvent which is inert under the reaction conditions, forexample a C₁ -C₆ alkanol, e.g. ethanol or methanol.

If desired, the removal of the activating group, and the cleavage ofsuitable derivatives of one or both of the carboxy groups to carboxygroups may be carried out concurrently, for example, using sulphuricacid.

The compounds of formula II are novel and may be made by an entirelynovel reaction which has no precedent in the literature.

Thus according to a further feature of the invention we provide aprocess for the production of a compound of formula II in which R ishydrogen, or a suitable derivative thereof, which comprises reaction ofa compound of formula III, ##STR4## or a suitable derivative thereof, inwhich R₅ and R₁₀ are as defined above, with a compound of formula IV,

    X--N═C═O                                           IV

in which X is as defined above.

The reaction may be carried out in a solvent which is inert under thereaction conditions, e.g. dichloroethane, dichloromethane oracetonitrile. The reaction may be carried out at a temperature of fromabout 15° C. to 150° C., e.g. the reflux temperature of the reactionmixture. We prefer to carry out the reaction using from 5 to 30% w/v ofthe compound of formula III in the solvent and using from about 0.8 to1.5, and preferably one, equivalent of the compound of formula IV foreach equivalent of the compound of formula III.

To produce a compound of formula II, in which R is alkyl, or a suitablederivative thereof, a corresponding compound of formula II, or asuitable derivative thereof, in which R is hydrogen may be alkylatedusing an alkylating agent, for example dialkyl sulphate, e.g. dimethylsulphate, alkyl tosylate, e.g. methyl tosylate or preferably an alkylhalide, e.g. methyl iodide, in a solvent which is inert under thereaction conditions, e.g. N-methylpyrrolidone, and in the presence of aproton acceptor, e.g. potassium carbonate.

We prefer the above reactions to be carried out using a derivative, forexample a salt, amide or more preferably an ester, of the carboxylicacid groups. Suitable salts include ammonium, alkali metal (e.g. sodium,potassium and lithium) and alkaline earth metal (e.g. calcium ormagnesium) salts, and salts with suitable organic bases, e.g. salts withlower alkylamines, such as methylamine or ethylamine. Suitable estersinclude simple lower alkyl esters, e.g. the ethyl ester, esters derivedfrom alcohols containing basic groups, e.g. di-lower alkyl aminosubstituted alkanols such as the 2-(diethylamino)-ethyl ester, andacyloxy alkyl esters, e.g. a lower acyloxy-lower alkyl ester such as thepivaloyloxymethyl ester. The suitable amides may be, for example,unsubstituted or mono- or di- C1 to C₆ alkyl or phenyl amides.

The compounds of formula I and pharmaceutically acceptable derivativesthereof are of known utility as pharmaceuticals, e.g. as anti-allergiccompounds.

Pharmaceutically acceptable derivatives of the compounds of formula Iinclude pharmaceutically acceptable salts, esters and amides of the 2-and/or 8-carboxylic acid group. Suitable salts include ammonium, alkalimetal (e.g. sodium, potassium and lithium) and alkaline earth metal(e.g. calcium or magnesium) salts, and salts with suitable organicbases, e.g. salts with hydroxylamine, lower alkylamines such asmethylamine or ethylamine, with substituted lower alkylamines, e.g.hydroxy substituted alkylamines such as tris(hydroxymethyl)methylamine,with simple monocyclic nitrogen heterocyclic compound, e.g. piperidineor morpholine, with an amino acid, e.g. lysine, ornithine, arginine, oran N-alkyl, especially an N-methyl derivative of any one thereof, orwith an aminosugar, e.g. glucamine, N-methylglucamine or glucosamine.Specifically included are compounds in which only one --COOH group is insalt form. Suitable esters include simple lower alkyl esters, e.g. theethyl ester, esters derived from alcohols containing basic groups, e.g.di-lower alkyl amino substituted alkanols such as the2-(diethylamino)-ethyl ester, and acyloxy alkyl esters, e.g. a loweracyloxy-lower alkyl ester such as the pivaloyloxymethyl ester. Thepharmaceutically acceptable acid addition salts of the compounds offormula I, e.g. the hydrochloride, the hydrobromide, the oxalate, themaleate or the fumarate salts, are also included. The amides may be, forexample, unsubstituted or mono- or di- C₁ to C₆ alkyl or phenyl amides.

We prefer compounds of formula I in which R₅ is hydrogen and R₁₀ is C₁to C₆ alkyl, specifically propyl.

We particularly prefer compounds of formula I in which R is alkyl C₁ toC₃, e.g. methyl.

We specifically prefer the compound of formula I in which R is methyl,R₅ is hydrogen and R₁₀ is propyl.

The compounds of formula I, and the intermediates therefor, may beisolated from their reaction mixtures using conventional techniqueswhich are known per se.

The invention is illustrated, but in no way limited by the followingExamples.

EXAMPLE 1 Diethyl6-methylamino-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate(a) Ethyl8-methoxycarbonyl-4-oxo-10-propyl-6(4-toluenesulphonamido)-4H-pyrano[3,2-g]quinoline-2-carboxylate

Ethyl6,9-dihydro-4,6-dioxo-8-methoxycarbonyl-10-propyl-4H-pyrano[3,2-g]quinoline-2-carboxylate(38.5 g, 0.1 mol) was suspended in dichloroethane (200 ml) and4-toluene-sulphonyl isocyanate (15.1 ml; 0.1 mol) added at roomtemperature. The whole was then refluxed for 16 hours, allowed to cool,and filtered, to give the sub-title compound as brilliant yellow cubes,44.0 g (82%), m.p. 219° C.

(b) Ethyl8-methoxycarbonyl-4-oxo-10-propyl-6(N-methyl-4-toluenesulphonamido)-4H-pyrano[3,2-g]quinoline-2-carboxylate

The product of step (a) (5.38 g, 0.01 mol) was suspended in N-methylpyrrolidone (40 ml), and potassium carbonate (1.38 g, 0.01 mol) added,to give on stirring at room temperature for five minutes a deep redsolution. Methyl iodide (2 ml) was then added, and the whole warmed to40° C., and stirring continued for one hour. The solution was pouredinto water (150 ml), to give the sub-title compound on filtration, as awhite powder, 5.44 g, (98.6%), m.p. 173°-174° C.

(c) Diethyl6-methylamino-4-oxo-10-propyl-4H-pyrano-[3,2-g]quinoline-2,8-dicarboxylicacid

The product of step (b) (5.52 g, 0.01 mol) was dissolved in concentratedsulphuric acid (98%, 5 ml) and warmed at 50° C. for one hour withvigorous stirring. The whole was then slowly poured into ethanol (50ml), and refluxed for 3 hours. This solution was then added slowly towater (35 ml) containing aqueous ammonia solution (0.88 specificgravity, 15 ml), to give a thick orange precipitate. Filtration gave thedesired product, 3.16 g (76%) as a pale orange powder, mp 235°-237° C.

EXAMPLE 2 Ethyl8-methoxycarbonyl-6-methylamino-4-oxo-10-propyl-4H-pyrano[3,2-g]-quinoline-2-carboxylate

The product of step 1(b) (10 g, 0.018 mol) was dissolved in sulphuricacid (98%, 20 ml) at room temperature. During dissolution the internaltemperature rose to 40° C., and the solution became deep red. Thesolution was then stirred for 2 hours, during which time the temperatureof the reaction fell to 25° C. The acidic solution was added toice/water (200 ml) over two minutes, the temperature being held below10° C. The aqueous solution formed was red-brown solution. After about 5minutes from the beginning of the addition a yellow precipitate formed.Aqueous ammonia solution (0.88 specific gravity) was added to thestirred yellow slurry, and as the pH rose, the slurry turned orange.Ammonia addition was ceased when the pH of the slurry reached 9. Theorange precipitate was filtered off, washed with water (50 ml), dried invacuo at 70° C. to give the title compound, 6.8 g (95%), which highperformance liquid chromatography (HPLC) showed to be 93.5% pure.N.m.r., CDCL₃, δ: 8.6, s, 1H; 7.1, s, 1H; 7.05, s, 1H, 5.85, broad q,1H; 4.45, q, 2H; 3.95, s, 3H; 3.75, t, 2H; 3.15, d, 2H; 1.8, m, 2H; 1.5,b, 3H; 1.05, t, 3H.

EXAMPLE 36-Methylamino-4-oxo-10-propyl-4H-pyrano[3,2-g]-quinoline-2,8-dicarboxylicacid

The product of step 1(b) (5 g, 0.009 mol) was dissolved in sulphuricacid (98%, 50 ml) and then heated to 100° C. Heating at 100° C. wasmaintained for 18 hours, then the solution was cooled to 30° C., andadded to ice/water (500 ml), to give a yellow precipitate. Theprecipitate was isolated by filtration, washed with water (100 ml), anddried in vacuo at 60° C. over 16 hours to give 3.0 g (93%) of the titlecompound. HPLC of the product, eluting with ammonium acetate/methanolestablished identity of the compound using the known disodium salt ofthe title compound as reference, and showed a purity of 95%.

EXAMPLE 4 Ethyl6-amino-8-methoxycarbonyl-4-oxo-10-propyl-4H-pyrano[3,2-g] quinoline-2carboxylate (a) Ethyl6(4-chlorophenoxysulphamido)-8-methoxycarbonyl-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2-carboxylate

4Chlorophenoxysulphonylisocyanate (2.0 ml, 2.90 g) was added to asuspension of ethyl6,9-dihydro-4,6-dioxo-8-methoxycarbonyl-10-propyl-4H-pyrano[3,2-g]quinoline-2-carboxylate(3.85 g, 10 mmol) in dichloroethane (20 ml), and then refluxed for 4hours. Removal of the solvent by distillation in vacuo, and triturationwith ether gave the desired product, 5.05 g (88%), as yellow crystals.

Microanalysis: C₂₆ H₂₃ ClN₂ O₉ S: calculated C: 54.31%, H: 4.00%, N:4.87%. found C: 53.96%, H: 3.99%, N: 4.79%.

(b) Ethyl6-amino-8-methoxycarbonyl-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2carboxylate

The product of step (a) (1.0 g) was dissolved in ethanolic hydrogenchloride (50 ml), and refluxed for 0.2 hours. The pale yellow solutionwas poured into aqueous ammonia solution (100 ml), cooled to 0° C., andthe orange precipitate obtained, filtered, washed with water, to givethe desired product as an orange powder, 0.55 g, mp 267°-270° C.(decomposes).

EXAMPLE 5 Ethyl6-amino-8-methoxycarbonyl-4-oxo-10-propyl-4H-pyrano[3,2-g]-quinoline-2-carboxylate(a) Ethyl8-methoxycarbonyl-4-oxo-10-propyl-6-trichloroacetamido-4H-pyrano[3,2-g)quinoline-2-carboxylate

Trichloroacetyl isocyanate (1.18 ml, 10 mmol) was added to a solution ofethyl6,9-dihydro-4,6-dioxo-8-methoxycarbonyl-10-propyl-4H-pyrano[3,2-g]quinoline-2-carboxylate(3.85 g, 10 mmol) in dichloromethane (20 ml) at room temperature. Thesolution was then agitated gently for 24 hours at room temperature andthen the solvent removed by distillation in vacuo. Trituration of theresulting solid with ether gave the sub-title compound as yellow cubes,4.25 g (80%), mp 167°-169° C.

(b) Ethyl 6-amino-8-methoxycarbonyl-4-oxo-10-propyl-4H-pyrano[3,2-g]-quinoline-2-carboxylate

The product of step (a) (1.0 g) was dissolved in concentrated sulphuricacid (1 ml) and stirred vigorously for 0.5 hours. The deep rep solutionwas then poured into iced aqueous ammonia solution (100 ml), and theprecipitate filtered to give the title compound, 0.5 g, as an orangepowder, mp 265°-270° C. (decomposes).

EXAMPLE 6 Ethyl6-amino-8-methoxycarbonyl-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2-carboxylate

4-Chlorophenoxysulphonylisocyanate (0.2 ml, 290 mg) was added to asuspension of ethyl6,9-dihydro-4,6-dioxo-8-methoxycarbonyl-10-propyl-4H-pyrano[3,2-g]quinoline-2-carboxylate(385 mg, 1 mmol) in acetonitrile (5 ml), and then refluxed for 0.5 h.The solution was allowed to cool, ethanolic hydrogen chloride solution(2 ml) was added, and after 5 minutes the pale yellow solution waspoured into aqueous ammonial solution (0.88 specific gravity, 5 ml) at5° C., to give a thick orange precipitate. Filtration and washing withethanol (10 ml) gave the title compound, 320 mg (83%) as an orangepowder, mp 268°-270° C. (decomposes).

I claim:
 1. A compound of the formula ##STR5## in which R is hydrogen oralkyl C₁ to C₆ and R₅ and R₁₀, which may be the same or different arehydrogen or alkyl C₁ to C₆,X represents a group --AR₆, A is CO or SO₂and R₆ is halogen, haloalkyl C₁ to C₆, alkoxy C₁ to C₆, phenoxyoptionally substituted by halogen or phenyl optionally substituted byalkyl C₁ to C₆, or a salt, ester or amide thereof.
 2. A compoundaccording to claim 1 wherein X is 4-toluenesulphonyl.
 3. A compoundaccording to claim 1, wherein R₅ represents hydrogen and R₁₀ representspropyl.